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US8143029B2 - Methods and means related to diseases - Google Patents

Methods and means related to diseases Download PDF

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US8143029B2
US8143029B2 US12/086,712 US8671206A US8143029B2 US 8143029 B2 US8143029 B2 US 8143029B2 US 8671206 A US8671206 A US 8671206A US 8143029 B2 US8143029 B2 US 8143029B2
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ctcl
genes
gene
pbmc
expression
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US20100035971A1 (en
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Annamari Ranki
Sonja Hahtola
Leena Karenko
Soile Tuomela
Riitta Lahesmaa
Kai J. E Krohn
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Valipharma Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to the fields of genetics and oncology and provides methods for detecting cutaneous T-cell lymphomas (CTCL) or susceptibility to CTCL.
  • CTCL cutaneous T-cell lymphomas
  • the present invention relates to a novel method for the diagnosis and follow-up of CTCL or CTCL subtype, the method comprising determination of expression of one or more genes, gene fragments or gene products.
  • the present invention further relates to a novel method of detecting the response to CTCL therapy, the method comprising determining expression of one or more genes or gene fragments or gene products in a biological sample.
  • the present invention further relates to a novel method of developing or improving CTCL therapy or developing anti-CTCL medicament, the method comprising screening agents affecting one or several of the genes or gene products.
  • the present invention further relates to a novel method of treating CTCL patients, the method comprising affecting one or several of the genes or gene products.
  • the present invention further relates to a novel test kit, the kit comprising the necessary means for detecting one or more genes, gene fragments or gene products.
  • the present invention also relates to a use of one or more genes, gene fragments or gene products for determination, diagnosis or follow-up of CTCL or CTCL subtype and for detection of the response to CTCL therapy.
  • the present invention also relates to a use of one or more target molecules for CTCL therapy or for the preparation of a medicament for treating CTCL.
  • CTCL Primary cutaneous T-cell lymphomas
  • MF mycosis fungoides
  • SzS Sezary syndrome
  • MF Mycosis fungoides
  • CTCL may also present in a leukaemic form with erythrodermic skin involvement and lymphadenopathy (Sezary syndrome, SzS), and 10-20% of MF cases transform to large T-cell lymphoma with time (Willemze R et al. Blood 90:354-371, 1997, Willemze R et al. Blood 105:3768-3785, 2005).
  • Helper T (Th) cells are essential for developing an immune response by activating antigen-specific effector cells and recruiting cells of the innate immune system such as macrophages and mast cells. Th1 commitment relies on the local production of IL-12, and Th2 development is promoted by IL-4 in the absence of IL-12. Th1 cells participate in cell-mediated immunity and control intracellular pathogens. The cytokines produced by Th1 cells stimulate phagocytosis and destruction of microbial pathogens. Th2 cells are essential for antibody-mediated immunity by stimulating the production of antibodies. Thus, Th2 cells participate in controlling extracellular pathogens.
  • Th1 responses are involved in many autoimmune diseases, whereas excessive Th2 responses are known to lead for example to chronic diseases, including allergies, asthma, and chronic bronchitis.
  • Increased Th2 cytokine levels have also been revealed in various malignancies including CTCL (Kari L et al. J Exp Med 197:1477-1488, 2003).
  • An object of the present invention is to provide novel solutions for the above problems.
  • the object of the invention is to provide novel methods and means for detecting CTCL or susceptibility to CTCL, such methods and means allowing an early diagnosis of the disease.
  • Another object of the invention is to provide novel methods and means for the prediction, diagnosis and follow-up of CTCL or CTCL subtype, such methods and means being specific and reliable and allowing identification as early as possible.
  • Yet another object of the invention is to provide novel methods and means for detecting the response to CTCL therapy, such methods and means allowing selection of specific and effective treatment for a patient.
  • Still another object of the invention is to provide novel biomarkers useful in detection of CTCL or potential for developing CTCL.
  • Still another object of the invention is to provide novel biomarkers useful in diagnosing CTCL or CTCL subtype as well as following up CTCL or CTCL subtype.
  • Still another object of the invention is to provide novel biomarkers useful in detecting the response to therapy of CTCL.
  • Still another object of the invention is to introduce new possibilities for combating the disease and for the recovery of the patient by providing novel biomarkers useful as target molecules for therapies or prevention of CTCL.
  • Still another object of the invention is to provide a diagnostic kit for detecting novel CTCL associated genes, gene fragments or gene products.
  • Yet another object of the invention is to provide novel methods and means for developing or improving CTCL therapy.
  • Still another object of the invention is to provide novel methods and means for developing anti-CTCL medicament.
  • Yet another object of the invention is to provide novel methods and means for treating CTCL.
  • the present invention relates to a novel method for detection of CTCL or susceptibility to CTCL, characterized by determining expression of one or more genes, gene fragments or gene products selected from the group comprising or consisting of S4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9 in a biological sample, whereby under- or overexpression of one or more of said genes, gene fragments or gene products indicates CTCL or susceptibility to CTCL.
  • the present invention relates to a novel method for detection of CTCL or susceptibility to CTCL, characterized by determining expression of MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9 genes, gene fragments or gene products in a biological sample, whereby under- or overexpression of one or more of said genes or gene products indicates CTCL or susceptibility to CTCL.
  • the present invention further relates to a novel method for the diagnosis and follow-up of CTCL or CTCL subtype, characterized by determining expression of one or more genes, gene fragments or gene products selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9 in a biological sample, whereby under- or overexpression of one or more of said genes, gene fragments or gene products indicates CTCL or susceptibility to CTCL or CTCL subtype.
  • the present invention further relates to a novel method of detecting the response to CTCL therapy, characterized by determining expression of one or more genes, gene fragments or gene products selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9, in a biological sample, whereby normalization of under- or overexpression of one or more of said genes, gene fragments or gene products indicates response of CTCL therapy.
  • the present invention further relates to a novel diagnostic kit, characterized by comprising the necessary means for detecting one or more genes, gene fragments or gene products selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9.
  • the present invention further relates to uses of one or more genes, gene fragments or gene products selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9 for determining CTCL, for the diagnosis and follow-up of CTCL or CTCL subtype, and for detecting the response to therapy of CTCL.
  • the present invention further relates to a use of one or more genes, gene fragments or gene products selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5 and LIR9 as target molecules for CTCL therapy.
  • the present invention also relates to a method for developing or improving CTCL therapy, the method comprising screening of agents affecting one or several of the genes or gene products selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9, whereby an agent having said effect allows developments and improvements of CTCL therapy.
  • the present invention also relates to a method for developing anti-CTCL medicament, the method comprising screening of agents affecting one or several of the genes or gene products thereof selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9, whereby an agent having said effect is tested as a medicament.
  • the present invention also relates to a method for treating CTCL patients, characterized by affecting one or several of the genes or gene products selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9.
  • FIG. 1 shows substantial differences that were observed in gene expression profiles in SzS PBMC, MF CD4+ and skin biopsy samples, compared to corresponding control samples.
  • SzS PBMC A
  • B MF skin biopsies
  • C MF CD4+ cells
  • D MF PBMC
  • E MF skin biopsies
  • F MF CD4+ cells
  • G MF PBMC
  • H MF PBMC
  • FIG. 2A shows genes distinguishing between Sezary syndrome (P1-4) and mycosis fungoides (P5-9). The analysis was performed by comparing the Sezary syndrome and mycosis fungoides PBMC samples together and selecting the genes distinguishing these two subtypes. The genes that were also differentially regulated between control samples and either Sezary syndrome or mycosis fungoides samples were included in the final data.
  • FIG. 2B shows a subset of genes found to change in a similar manner both in SzS (P1-4) and MF (P5-9) PBMC samples when compared to controls (C1-5).
  • FIG. 3A shows quantitative PCR, performed on 10 genes.
  • FIG. 3B shows the downregulation of TBX21 gene in PBMC samples of both SzS (P1-4 and SzS1-2) and MF patients (P5-9 and MF1).
  • FIG. 4A shows gene expression profiles by chromosome arms in four SzS PBMC (patients P1-4) and three MF skin samples (patients P5, P7, P8).
  • FIG. 4B shows gene expression ratios of Szs PBMC and MF PBMC mapped to chromosome 12q.
  • FIG. 4C shows combined CGH profiles of three Sezary syndrome (blood samples) and three mycosis fungoides (skin samples) patients.
  • FIG. 5 shows that the gene expression profile reflected the size of tumor burden in an SzS patient.
  • the gene expression profile of patient P2 (Table 1) was analyzed before (pre thr) and after (post thr) cancer therapy.
  • the probe sets differentially regulated in SzS and control PBMC samples, a group of probe sets changed over 2-fold towards the control phenotype as a consequence of successful treatment.
  • the upregulated (A) and down-regulated (B) probe sets are presented as compared to the average expression of these probe sets in all patient samples.
  • the changes in gene expression correlated with the clinical phenotype of the patient before (C) and after (D) treatment.
  • the percentage of Sezary cells of blood lymphocytes is indicated in the inserts.
  • FIGS. 6A-D show immunohistochemical detection of CD52 and IL7R, found upregulated at RNA level, in lesional mycosis fungoides and Sezary syndrome skin samples before therapy.
  • MS4A4A Aberrant regulation of one or several genes or gene products, specifically MS4A4A, NKG7 (also known as GIG1), IL7R (also known as IL7R-ALPHA or CD127), CD52, TBX21 (also known as TBET), SCYA5 (also known as CCL5 or TCP228), and LIR9 (also known as ILT11 or CD85F), is associated with CTCL.
  • GIG1 also known as GIG1
  • IL7R also known as IL7R-ALPHA or CD127
  • CD52 also known as TBX21 (also known as TBET)
  • SCYA5 also known as CCL5 or TCP228)
  • LIR9 also known as ILT11 or CD85F
  • the present invention is based on a method of detecting CTCL or susceptibility to CTCL by determining differential regulation of one or more genes or gene products selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9.
  • CTCL or CTCL subtype is mycosis fungoides (MF) or Sezary syndrome (SzS).
  • over- or underexpression of one or several of the genes is characteristic of Th1 or Th2 polarization.
  • over-expression of LIR9 is characteristic of Th2 polarization.
  • under-expression of NKG7, TBX21 or SCYA5 is characteristic of Th2 polarization.
  • under- or overexpression indicates the early stage of CTCL.
  • under- or overexpression indicates the late stage of CTCL.
  • genes, gene fragments or gene products that is one or several genes, gene fragments or gene products listed in Tables 2 or 3, is determined.
  • the present invention is also based on a diagnostic kit comprising the necessary means for detecting one or more genes, gene fragments or gene products selected from the group comprising MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9.
  • the test kit comprises the necessary means for detecting genes MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9 or gene fragments or gene products thereof.
  • gene product refers to a mRNA, protein or to any product achieved directly or indirectly from the gene.
  • gene fragment refers to any part of a gene or an incomplete or isolated portion of a gene, which is detectable in the methods of the invention.
  • over- and underexpression refer to up- or down-regulation of a gene or gene products, correspondingly.
  • biological sample refers to any suitable tissue sample, such as whole blood or biopsy from the tissue or lymph node.
  • the biological sample can be, if necessary, pretreated in a suitable manner known to those skilled in the art.
  • subtype refers to a restricted type of disease, functional disorder or defect such as mycosis fungoides or Sezary syndrome.
  • Th1 or Th2 polarization refers to a path, where pre-Th cells begin to proliferate, become activated, and depending on the stimulation gain characteristics of Th1 or Th2 cells and develop to Th1 or Th2 cells.
  • the expression “by screening agents” refers to any in vitro or in vivo method known by the man skilled in the art, which method can be used in evaluating or measuring the effect of an agent on genes or gene products.
  • the expression “necessary means for detecting genes, gene fragments or gene products” refers for example to any markers, probes, primers, antibodies as well as standards, labels, buffers, diluents, and washing solutions suitable for detection.
  • the expression also refers to compositions or diagnostic kits, which are provided for example in the form of an ELISA, protein chip, nucleic acid chip or a membrane loaded with DNA, RNA or protein, or any other composition known by the man skilled in the art.
  • diagnostic kits comprise instructions to carry out the methods for detecting genes, gene fragments or gene products.
  • Th1-specific genes such as SCYA5, NKG7, and TBX21 were found to be downregulated in SzS samples ( FIG. 1E ) and genes e.g. LIR9 and MS4A4A were found upregulated in both MF and SzS samples (Table 3).
  • IL7R and CD52 were upregulated.
  • Chromosomal arms 1q, 3p, 3q, 4q, 12q, 16p and 16q revealed amplified chromosomal areas and overexpressed genes. Chromosomal areas 4q and 12q also contain down-regulated genes and deleted areas.
  • the therapy-responsive genes included e.g. S100P, CCR10, BCL2, VAV3 and GZMB.
  • Differential regulation of genes, gene fragments or gene products can be caused by various events or mechanisms such as point mutations, polymorphisms, translocations, genetic or chromosomal deletions, insertions, gene or chromosomal amplifications, gene conversions and any other defects.
  • Silencing of genes or chromosomal areas can be caused for example by epigenetic mechanisms such as methylation.
  • expression of genes, gene fragments, and gene products can be detected in a biological sample by any known suitable detection method.
  • detection methods comprise detecting a gene expression or methods based on detecting the copy number of the gene, DNA or chromosome and/or those based on detecting the gene expression products (mRNA or protein).
  • Such methods are easily recognized by those skilled in the art and include for example enzymatic methods, electrophoretic methods or physical methods such as conventional polymerase chain reaction (PCR)-methods, RT-PCR, real time quantitative PCR, single strand conformation polymorphism (SSCP), heteroduplex analysis, fragment analysis, DNA sequencing, minisequencing, primer extension methods, microarrays, mass spectrometry and denaturing high performance liquid chromatography (DHPLC).
  • suitable methods include conventional G-banding techniques, comparative genomic hybridization (CGH), in situ hybridisations, such as FISH, mRNA in situ hybridization, Northern analysis, and Southern as well as Western analyses, immunohistochemistry, and other immunoassays, such as ELISA.
  • Epigenetic assays such as methylation assays may also be used.
  • markers suitable for detecting differential gene regulation include any biological markers such as microsatellite markers, SNP-markers, any probes, primers or antibodies associated with genes or gene products.
  • diagnostic tests based on the current findings, may also have implications in the tests for screening patients for eventual subclinical forms of CTCL. Such screening tests may be based on the detection of secretory proteins upregulated in CTCL. Furthermore, any diagnostic test developed on basis of the currently revealed genetic alterations in CTCL may be used to monitor or predict the disease outcome, to predict the drug responsiveness of the patients and in clinical follow-up.
  • the current finding of up- and downregulation of specific genes in CTCL can also be used in the field of therapy, when restoration of the normal function of genes can be used. This may be reached by enhancing the expression of functionally homologous genes, by introducing an intact gene or by using an altered form of the gene or antisense oligonucleotide or small inhibitory RNA against the gene or gene product in any technique presently available for gene therapy to prevent the progression of a proliferating disease.
  • Such techniques include the in vivo, ex vivo and in situ therapy methods comprising transducing or transfecting an intact or altered gene (or its functional domains) in a recombinant or peptide form or as antisense oligonucleotides or in an expression vector to the patient or inserting the altered gene or oligonucleotide into a carrier, which is then introduced into the patient. It is noteworthy that the delivery of those genes, which are hoped to be expressed in a therapeutic manner can be achieved by epicutaneous delivery of naked DNA vectors expressing the gene of interest.
  • One possible way to express a therapeutic gene would be to use viral vectors, especially ones with a preferential homing to skin and dermis.
  • monoclonal or humanized antibodies, modified antibodies or peptides binding to the protein or to the fusion gene generated can be used to suppress the function of the altered protein.
  • Antibodies against the protein could also be used to carry and target other agents, such as cytotoxic substances, to specific cells.
  • a transient or a permanent cure of CTCL may be achieved by above-mentioned methods.
  • Such drugs may be monoclonal antibodies targeted against membrane proteins that are expressed on the malignant cells or against secretory proteins that in turn affect the host regulatory processed, such as immune response against the malignant cells.
  • monoclonal antibodies or other response modifiers may be targeted against secretory products of the malignant cells that favor the spread of the tumor.
  • An important group of target molecules for therapeutic approaches for CTCL are the genes and gene products involved in immune regulation.
  • Th1-specific genes Downregulated in SzS, TBX21 and TXK represent transcription factors essential for Th commitment to Th1 phenotype. They both regulate IFN ⁇ expression, the expression of which we have previously shown to be absent from the chromosomally clonal, i.e. true malignant cells in SzS (Karenko L et al. J Invest Dermatol 116:188-193, 2001). Also, they belong to a positive feedback loop promoting Th1 cytokine secretion leading to Th1 development (Szabo S J et al. Cell 100:655-669, 2000, Takeba Y et al. J Immunol 168:2365-2370, 2002).
  • TBX21 The expression of TBX21 was very low also in one MF patient, but the overall variation among MF patients, representing various stages, was greater than among the leukaemic SzS patients. Recently, TBX21 has also been shown to regulate the CD4+ cell trafficking to inflammatory sites, by regulating e.g. the expression of the chemokine ligand CXCR3 (Lord G et al. Blood 106:3432-3439, 2005), but TBX21 has not been linked to CTCL before. Our finding of TBX21 downregulation in SzS thus explains the previous observation of the loss of CXCR3 expression along the progression of MF (Appay V and Rowland-Jones SL. Trends Immunol 22:83-87, 2001).
  • S100P has a role in cell cycle progression and differentiation, and its upregulation has been found in various malignancies (Vowels B R et al. J Invest Dermatol 103:669-673, 1994, Dummer R et al. Blood 88:1383-1389, 1996, Cairns C M et al. J Immunol 167:57-65, 2001, and Dohring C et al.
  • LIR9 is a member of leukocyte immunoglobulin-like receptor family mostly expressed on monocytes and neutrophils but not on normal T cells. In monocytes, activation of LIR9 has been shown to induce calcium mobilization and secretion of IL-1 ⁇ , TNF- ⁇ and IL-6 (Gardiner C M et al.
  • IL-6 has been shown to be a marker of SzS tumor burden and to correlate with clinical stage in non-leukemic CTCL (Sato N et al. Oncogene 23:1531-1538, 2004).
  • IL-6 is an important cytokine for Th2 cell differentiation (Hammacher A et al. Int J Biochem Cell Biol 37:442-450, 2005), but also induces S100P (Cairns C M et al. J Immunol 167:57-65, 2001).
  • KIR3DL2 a member of the killer cell immunoglobulin-like receptors, has previously been suggested as a phenotypic marker for Sezary cells (Poszepczynska-Guigne E et al. J Invest Dermatol 122:820-823, 2004) and has been found upregulated in SzS (van Doorn R et al. Cancer Res 64:5578-5586, 2004). Contradictory, we found KIR3DL2 gene to be downregulated in SzS. However, the LIR9 gene, located in the same leukocyte receptor cluster as KIR3DL2 was overexpressed. This discrepancy of observations may be due to the considerable polymorphism of the KIR3DL2 gene (Jones D et al. Clin Cancer Res 10:5587-5594, 2004, Duvic M et al. Am J Hematol 58:87-90, 1998). Thus, our data provide evidence for the downregulation of several cytotoxicity-associated genes in SzS.
  • IL2R ⁇ we found IL2R ⁇ to be downregulated in SzS blood samples, which is of interest since IL2 is the major cytokine for T-cell activation and proliferation.
  • IL2R consists of three subunits, of which IL2R ⁇ and IL2R ⁇ are expressed on resting T-cells and upregulated by e.g. IL-2.
  • the high/intermediate affinity IL2R ⁇ /p55/CD25+ ⁇ /p75/CD122+ ⁇ /p64/CD132 chains/ ⁇ + ⁇ chains
  • CTCL cells Olsen E et al. J Clin Oncol 19:376-388, 2001, Duvic M. Algorithms.
  • MS4A4A was upregulated on SzS cells.
  • Another member of this superfamily, CD20 is already now the target of monoclonal antibody mediated therapy in large B-cell lymphomas (Press O W et al. Blood 69:584-91, 1987).
  • the MS4A4A is useful as a target molecule for therapy of SzS.
  • LIR9 (215838_at) Another potential target membrane protein is LIR9 (215838_at) found to be over expressed on SzS. Similarly to MS4A4A, specific monoclonal antibodies against LIR9 (215838_at), preferentially humanized or hybrid forms, are useful as a therapeutic principle.
  • LIR9 (215838_at) is another potential target membrane protein.
  • MS4A4A specific monoclonal antibodies against LIR9 (215838_at), preferentially humanized or hybrid forms, are useful as a therapeutic principle.
  • several other potential forms of drug acting on membrane proteins can be designed, based on the findings in this patent application, such forms being for example aptomeres or agonistic peptides.
  • genetically altered natural ligands for the membrane protein that inhibits or strengthens the action of the natural ligand may be used as a therapeutic principle.
  • S100P Another potential target molecule for therapeutic approaches is the S100P gene, which has a role in cell cycle progression and differentiation. Its upregulation has been found in various malignancies (Vowels B R et al. J Invest Dermatol 103:669-673, 1994, Dummer R et al. Blood 88:1383-1389, 1996, Cairns C M et al. J Immunol 167:57-65, 2001, and Dohring C et al. Immunogenetics 44:227-230, 1996) and its expression is regulated by steroid hormones, notably by androgens and progestins. We propose therefore that similar principles are useful for therapy of CTCL.
  • SNCA is a major component of protein aggregates present in Parkinson's disease (Mao X et al. Br J Dermatol 147:464-475, 2002).
  • the present invention discloses for the first time the role of at least one or several of the genes MS4A4A, NKG7, IL7R, CD52, TBX21, SCYA5, and LIR9 in CTCL.
  • the present invention also discloses that detection of up- or down-regulation of these genes or gene products allows identification of CTCL patients or patients with an increased risk to develop CTCL.
  • Discoveries of novel diagnostics and follow-up methods reveal new possibilities in the field of CTCL medicine.
  • PBMC samples were obtained from 12 Sezary syndrome and mycosis fungoides patients and lesional skin biopsies from 9 mycosis fungoides patients (stage IA-IVB; defined according to the WHO-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas; Willemze R et al. Blood 105:3768-3785, 2005).
  • Affymetrix (Santa Clara, Calif.) analysis was done for 6 PBMC or CD4+-enriched cell samples of four Sezary syndrome patients and for 11 PBMC, CD4+, or skin lesion samples of five mycosis fungoides patients (Table 1).
  • the percentage of Sezary cells (medium-sized lymphoid cell with a highly cleaved “cerebriform” nucleus and darkly clumped chromatin) among peripheral blood lymphocytes of Sezary syndrome patients ranged from 16% to 70%. None of the Sezary syndrome patients had received any anticancer therapy before sampling.
  • PBMC Peripheral blood mononuclear cells
  • PBMC Peripheral blood mononuclear cells
  • Ficoll Paque density gradient centrifugation Ficoll-Paque PLUS, Amersham Biosciences, Uppsala Sweden
  • CD4 positive cells were enriched with magnetic beads (CD4+ T-cell isolation kit #130-053-101, or CD4+ MicroBeads #130-045-101, Miltenyi Biotec, Bergisch Gladbach, Germany).
  • Total RNA was isolated with Trizol Reagent (Invitrogen, Life Technologies, Grand Island, N.Y.).
  • RNA 100 ng of purified (RNeasy Mini, Qiagen, Valencia, Calif.) RNA was prepared for hybridization according to Affymetrix small sample protocol (Affymetrix Technical note, GeneChip® Eucaryotic Small Sample Target Labelling Assay Version II). cDNA was hybridized against Affymetrix HG-U133A chip (Affymetrix, Santa Clara, Calif.). Gene expression estimates were calculated using the GC-RMA procedure (Wu Z et al. Journal of the American Statistical Association 99:909-917, 2004). In each two-group comparison, the statistical significance of the difference in gene expression levels between the groups was assessed with a modified t-test (Smyth GK. Statistical Applications in Genetics and Molecular Biology 3:Article 3, 2004).
  • a gene was considered changed if the p-value of the test was less than 0.05 and there was at least a 2-fold change in the mean expression levels.
  • the statistical analyses were carried out with R (cran.r-project.org) packages Affy and Limma and visualization with the TreeView software (Eisen M B et al. Proc Natl Acad Sci USA 95:14863-14868, 1998).
  • Patient-specific gene expression profiles were constructed by calculating gene expression ratios between each patient and the average of the matched controls. To assess regional biases in the expression profiles, the microarray probe sets were mapped along the chromosomes using the Bio-conductor annotation package hgu133a. To determine whether the set of expression ratios that map to a particular chromosomal arm exhibit upward or downward bias, a sign test was applied (Crawley J J and Furge K A. Genome Biol 3:RESEARCH0075, 2002). The algorithm scores a gene as up- or down-regulated if the expression change is at least 1.8-fold, and the sign test determines whether the corresponding chromosomal arm contains a statistically significant number of genes that change in the same relative direction. An expression bias was considered significant if the p-value of the sign test was less than 0.05. Of the acrocentric chromosomes only q-arms were included in the analysis.
  • FIG. 1A shows differentially regulated genes in all studied cell populations with fold change exceeding the value 3
  • FIG. 1B shows substantial variation of gene expression between control and MF skin samples
  • Th1-specific genes SYA5 and NKG7
  • IL-2R ⁇ , VAV3, DLG5, and KIR3DL2 were found to be over 2-fold downregulated in SzS samples ( FIG. 1E ).
  • Genes upregulated in both MF and SzS blood samples included e.g. S100P and MMP-9.
  • IL7R and CD52 were upregulated.
  • SNCA and LIR9 genes were upregulated in several cell populations of SzS and MF patients (Table 2).
  • TBX21 was selected for further analysis based on its crucial role in Th1 differentiation.
  • RNA samples were treated with Deoxyribonuclease 1, Amplification grade (Invitrogen Life Technologies, Carlsbad, Calif.) to eliminate possible genomic DNA and the purity of RNA was checked with RT run.
  • the cDNA was prepared with Superscript II kit (Gibco BRL, Life Technologies, Paisley, Scotland).
  • TBX21, NKG7, SCYA5, SLOOP, and house keeping gene EF1 ⁇ were run with FAM (reporter) and TAMRA (quencher) duallabeled probes and other genes with ProbeLibrary probes (Exiqon A/S, Vedbaek, Denmark). Primer and probe sequences are listed in table 4.
  • Immunostainings for CD52 (Abcam, Cambridge, UK, diluted in 1:100), IL7R (R&D Systems, MN, USA, 1:10), IL7 (R&D Systems, 1:20), and KLK10 (R&D Systems, 1:30) were performed with Vectastain Elite Mouse kit (Vector Laboratories, Burlingame, Calif.), according to manufacturer's instructions.
  • the immunostainings were carried out on frozen tissue sections of four CTCL patients included in the Affymetrix study, of 5 additional CTCL patients, and of 5 controls with eczema or lichen planus.
  • MMP9 immunostaining was performed on formalin fixed paraffin embedded tissue sections of six CTCL patients included in the Affymetrix study and on controls with lichen planus and psoriasis using a mouse monoclonal antihuman MMP9 antibody (Research Diagnostics Inc, Flanders, N.J.; diluted in 1:50) as previously described by Saarialho-Kere and coworkers 1993.
  • Quantitative PCR performed on 10 genes ( FIG. 3 ), and immunohistochemistry, performed on four gene products (CD52, IL7R, IL7, MMP-9), validated the microarray data ( FIGS. 6A-D ).
  • KIR3DL2 previously reported to be a marker gene of CTCL (Poszepczynska-Guigne E et al. J Invest Dermatol 122:820-823, 2004), and now found downregulated in our SzS patients, were not due to differences in target sequence.
  • CD52 protein was expressed by the majority (in average, 3 of 4) of skin-infiltrating lymphocytes of all CTCL patients when compared with inflammatory dermatoses with sparse expression.
  • IL7R was expressed in basal keratinocytes (focally) but also in skin-infiltrating lymphocytes of all CTCL biopsies. The number of lymphocytes or keratinocytes expressing IL7R was, in average, thrice higher than in control samples. No difference in the expression levels of IL7 protein was found between CTCL patients and controls.
  • MMP-9 protein was demonstrable in 25% to 50% of infiltrating lymphocytes in Sezary syndrome samples, whereas MMP-9 expression in mycosis fungoides samples was variable. In inflammatory dermatoses, the lymphocytes did not express MMP-9.
  • CGH was performed as previously reported (Karenko L et al. J Invest Dermatol 112:392-395, 1999) from the DNA of three SzS and three MF patients (Table 1).
  • MFISH metaphase preparations from cases 1-3, 5, 7, and 8, was performed as described previously (Karenko L et al. Cancer Res 65:8101-8110, 2005). At least 50 metaphases were analyzed for each case.
  • FIG. 4A illustrates the gene expression ratios mapped to chromosome 12q. Clusters of differentially expressed genes can be visualized especially in the areas 12q13 and 12q23-q24.
  • the chromosomal regions identified with the sign test were compared to the chromosomal aberrations detected by CGH.
  • a significant gain was detected also by the CGH analysis in at least four of the MF skin and SzS blood samples.
  • the SNCA gene found to be upregulated locates to cytoband 4q21.
  • chromosomes 3p, 3q, and 12q a significant gain was detected in at least two of the samples, and in 16p, in one sample.
  • chromosomes 4q and 12q where also downward expression bias was identified, a loss was detected by CGH in one and two of the samples, respectively ( FIG. 4C ).
  • a follow-up PBMC sample of one of the Sezary syndrome patients (case 2, described in Example 1a, Table 1) was obtained 19 months after a continuous therapy resulting in clinical response.
  • the probe sets differentially regulated in SzS PBMC samples, when compared to control PBMC samples, a group of 57 probe sets was changed towards the control phenotype after successful therapy ( FIG. 5 ).
  • the therapy-responsive genes included e.g. S100P, CCR10, BCL2, VAV3 and GZMB.
  • Rho family activation DLG5 Downregulated Tumor suppressor Increases cell proliferation MMP-9 Upregulated Matrix metalloproteinase Carcinogenesis and tumour spread IL7R Upregulated Cytokine receptor Lymphocyte activation (basal and homing to keratinocytes) epidermis CD52 Upregulated Membrane antigen (target molecule of alemtuzumab) MS4A4A Upregulated Membrane antigen Signal transduction in haematopoietic cells

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